Glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory peptide) is one of two endogenous incretins and is a 42 amino acid peptide hormone released from intestinal K-cells following food intake. GIP and the other incretin, glucagon-like Peptide-1 (GLP-1), are gut enteroendocrine cell-derived hormones accounting for the incretin effect, which estimated to account for over 70% of the total insulin response to an oral glucose challenge.
Due to the incretin effect, the GIP receptor has become an attractive drug target in the treatment of metabolic diseases such as obesity and diabetes, with GIP receptor agonists either as a standalone, in combination with GLP-1 receptor agonists, or in combination with GLP-1/glucagon receptor co-agonists. GIP itself has a short plasma half-life due to dipeptidyl peptidase-4 (DPP-IV) mediated inactivation, and poor physical stability due to high tendency to form fibrils in solution.
Patent applications disclosing different GIP receptor agonists or and their potential medical uses are described, such as e.g. disclosed in WO 2016/066744, WO 2016/034186, WO 2012/055770, and WO 2012/167744. Also GIP/GLP-1 receptor co-agonists and their medical use have been studied in e.g. WO 2013/164483, and WO 2014/192284.
The derivatives of the present invention provide novel modified GIP analogues with a protracted profile of action in addition to providing improved stability.